1. Field of the Invention
The present invention relates generally to cancer therapy and, more particularly, to compositions and methods for sensitizing a cancer in a subject to radiation therapy.
2. Background Information
Improved methods and novel agents for treating cancer have resulted in increased survival time and survival rate for patients with various types of cancer. For example, improved surgical and radiotherapeutic procedures result in more effective removal of localized tumors. Surgical methods, however, can be limited due, for example, to the location of a tumor or to dissemination of metastatic tumor cells. Radiotherapy also can be limited by these factors, which limits the dose that can be administered. Tumors that are relatively radioresistant will not be cured at such a dose.
Immunotherapeutic methods also are being examined as a means to treat a cancer by stimulating the patient's immune response against the cancer. In particular, the role of cytokines, which are cellular factors that can modulate an immune response, is an important factor to consider when planning an immunotherapeutic procedure. For example, expression of a cytokine such as interleukin-2 (IL-2) can increase the proliferation of T cells, which are involved in the cellular immune response against a cancer.
It is well known, however, that cytokine administration frequently is associated with toxic effects that limit the therapeutic value of these agents. For example, severe hypotension and edema limit the dose and efficacy of intravenous and intralymphatic IL-2 administration. In addition, flu-like symptoms or fatigue often are associated with the administration of various cytokines. The toxicity of systemically administered lymphokines is not surprising as these agents mediate local cellular interactions and normally are secreted only in very small quantities.
To circumvent the toxicity of systemic cytokine administration, an alternative approach involving cytokine gene transfer into tumor cells has produced anti-tumor immune responses in several animal tumor models. In these studies, the expression of cytokines following cytokine gene transfer into tumor cells resulted in a reduction in tumorigenicity of the cytokine-secreting tumor cells when implanted into syngeneic hosts. Reduction in tumorigenicity has been reported in studies using, for example, IL-2, interferon-γ or interleukin-4. In addition, the treated animals often developed systemic anti-tumor immunity and were protected against subsequent tumor cell challenges with unmodified tumor cells.
Although a single treatment modality such as radiation therapy, chemotherapy, surgery or immunotherapy can result in improvement of a patient, superior results can be achieved when such modalities are used in combination. In particular, treatment with a combination of radiotherapy, which can be directed to a localized area containing a tumor, and chemotherapy or immunotherapy, which provide a systemic mode of treatment, can be useful where dissemination of the disease has occurred or is likely to occur. Unfortunately, the therapeutic usefulness of radiation therapy can be limited where the tumor cells are relatively radioresistant, since the does is limited by the tolerance of normal tissue in the radiation field. Thus, there exists a need to sensitize cancer tumors to the effects of radiotherapy so that it can more effectively reduce the severity of a tumor in a patient. The present invention satisfies this need and provides related advantages as well.